Abstract
The cancer-associated SF3B1K700E mutation induces DNA damage via generation of genotoxic R-loops and stalled replication forks, defective homologous recombination, and increased replication fork degradation, which can be targeted with PARP inhibitors.
Highlights
The DNA damage response (DDR) is a highly complex network of pathways that play an essential role in maintaining genome stability and protecting cells from malignant transformation
SF3B1 is required for an efficient DDR We have previously shown that the BRCA1 mRNA-splicing complex, which includes SF3B1, facilitates DNA repair, in part through its ability to promote the efficient splicing of genes involved in the DNA damage response[1]
Given that SF3B1 is the most highly mutated member of this complex in a variety of cancers, we hypothesised that loss or mutation of this subunit would result in a DNA repair defect akin to what is observed in BRCA1 mutant tumours
Summary
The DNA damage response (DDR) is a highly complex network of pathways that play an essential role in maintaining genome stability and protecting cells from malignant transformation. We previously found that a key DDR protein, BRCA1, forms a DNA damage-inducible complex with several key splicing factors including BCLAF1 and SF3B1, to stimulate the premRNA splicing of a specific set of target genes, which function to facilitate DNA damage and DNA repair[1]. Of all the known spliceosome components SF3B1 is the most commonly mutated in human cancers. Mutations in this gene are recurrently observed in myelodysplastic syndromes (MDS) and other myeloid/lymphoid neoplasms, with the heterozygous missense substitution K700E being the most prevalent[2,3,4]. The role of SF3B1 mutations in disease progression remains controversial, with different roles played in different disease settings. The impact of these mutations on disease outcome is dependent on disease type and/or stage[10]
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